PROJECT SUMMARY This is a Supplement for Dr. Kara Maxwell's Mentored Clinical Scientist Development Award (K08-CA215312). K08-CA215312 was funded on 3/01/2018 and details a five year plan to promote the independent career of Dr. Kara Maxwell as a physician scientist in translational cancer genetics. Dr. Maxwell is a PhD trained molecular and cellular biologist who is board certified in Medical Oncology. Her clinical focus is in cancer risk evaluation. Dr. Maxwell is currently an Assistant Professor of Medicine at the University of Pennsylvania and is mentored for this K08 award in human genetics and genomics by Dr. Katherine Nathanson. Dr. Maxwell is interested in inherited susceptibility to cancer and, specifically, how inherited mutations in DNA repair genes can direct targeted treatment of cancer. Most tumors in patients with germline mutations in the homologous recombination DNA repair genes BRCA1/2, respond to platinum agents and PARP inhibitors due to synthetic lethality. However, tumors with primary and acquired resistance to these agents exist. Dr. Maxwell's preliminary studies showed that absence of BRCA locus-specific loss of heterozygosity (LOH) is observed in approximately 25% of primary BRCA1/2 germline mutation-associated breast and ovarian tumors. Her data suggest that BRCA1/2 locus-specific LOH could be a mechanism of primary platinum and PARP inhibitor resistance. K08-CA215312 aims to expand these preliminary studies into two clinically important categories of patients: 1) patients with inherited BRCA1/2 mutations with non-breast/ovarian tumors (Aim 1) and 2) breast cancer patients with inherited mutations in the DNA repair genes ATM and CHEK2, the two most commonly identified genes in BRCA1/2 negative breast cancer patients (Aim 2). Some tumors with primary resistance to platinum and PARP inhibitors demonstrate locus-specific LOH; therefore, other mechanisms exist. Hypomorphic, or partially functional, mutations may retain sufficient DNA repair activity to lead to primary resistance. Dr. Maxwell will test the hypothesis that hypomorphic BRCA2 mutations may demonstrate primary PARP inhibitor resistance using CRISPR-Cas9 modelling of mutations in breast cancer cell lines (Aim 3). She is supplementing these studies with a career development program that takes advantage of the resources of the Basser Center for BRCA Research and broadly at UPenn. Dr. Maxwell's long-term goal is to develop a career as a physician scientist running an independently funded laboratory studying inherited susceptibility to cancer. She has strong institutional support for this goal, and she was provided institutional startup funds and laboratory space upon her promotion to Assistant Professor on 07/01/2018. Unfortunately, three significant life events have led to difficulties at this critical period ? the death of her aunt for whom she was medical and financial power of attorney and now estate executor, and medical issues with her father and daughter. This administrative supplement providing funding for a Laboratory Manager will allow Dr. Maxwell to accelerate the pace of experiments and projects to continue to move forward in her career and establish independence.